Balloon Catheter Systems for Delivery of Dry Drug Delivery Vesicles to a Vessel in the Body

ABSTRACT

Devices and methods for balloon delivery of rapamycin and other hydrophobic compounds to the wall of blood vessels. Balloon catheters, such as those used for balloon angioplasty, are modified with the addition of a reservoir of dry micelles, disposed at a suitable location within the balloon or catheter. The reservoir may be installed within the angioplasty balloon, within a lumen in communication with the angioplasty balloon, either as a loose or packed powder or as a film coating. The micelle preparation is reconstituted and the micelles are mobilized when the aqueous solution used to inflate the balloons is injected into the catheter. The micelles are infused into tissue surrounding the balloon when pressurized fluid within the balloon leaks through the wall of the balloon.

This application is a divisional application of U.S. application Ser.No. 12/982,760, filed Dec. 20, 2010, which claims priority toProvisional Patent Application 61/291,345 filed Dec. 30, 2009.

FIELD OF THE INVENTIONS

The inventions described below relate to the field of treatment ofvascular disease, and more specifically to the field of drug elutingballoons for the treatment of restenosis.

BACKGROUND OF THE INVENTIONS

In the field of vascular disease, restenosis refers to the re-growth oftissue within a blood vessel which as been treated with angioplasty orstent placement, such that the blood vessel becomes occluded shortlyafter pre-existing blockages are cleared. Whether blood vessels aretreated with angioplasty alone, bare metal stents or drug elutingstents, restenosis is likely. To combat restenosis, various compoundshave been applied to treated blood vessel walls at the time of initialtreatment. These compounds includes rapamycin and paclitaxel and variousderivatives of these compounds. Typically, these compounds are deliveredto the blood vessel wall through balloons or through a drug-elutingcompound on the stent. Drug-eluting stents appear to forestallrestenosis, and late term thrombosis is a significant complication ofdrug eluting stents which must eventually be treated, perhaps withballoon delivery of additionally therapeutic agent. Balloon deliverythrough various mechanisms has been proposed, including (1) coatingballoons with a therapeutic compound and then inflating them within alesion to press the therapeutic compound into contact with thesurrounding blood vessel wall and (2) passing a therapeutic compoundthrough the porous wall of a balloon while the balloon is inflatedwithin the lesion in order to infuse the therapeutic compound into theblood vessel wall. For compounds such as paclitaxel, these techniquesappear useful at least to the extent that clinical experimentation iswarranted. However, due to inherent properties of rapamycin and itsanalogs or derivatives, e.g. hydrophobicity, direct delivery of thesedrugs from amorphous or crystalline coatings on the surface of anangioplasty balloon is inefficient.

SUMMARY

The devices and methods described below provide for effective balloondelivery of rapamycin and other hydrophobic compounds to the wall ofblood vessels. Balloon catheters, such as those used for balloonangioplasty, are modified with the addition of a mass of dry micelles,disposed at a suitable location within the balloon or catheter.Immediately prior to use, or during use, the mass of dry micelles isreconstituted with the addition of an aqueous solution into thecatheter. The balloon is then pressurized and the reconstituted micellesare forced out of the balloon through a porous wall of the balloon. Thedry micelle reservoir may be a powdered lyophilized micelle reservoir ora film, and it can be installed in the balloon catheter duringmanufacture of the balloon or after manufacture. The reservoir may beinstalled within the angioplasty balloon, or within a lumen incommunication with the angioplasty balloon, or in a storage chamber atthe proximal end of the catheter, either as a loose or packed powder oras a film coating. In addition, the dry micelles may be suspended inhydrogel or other stabilized non-aqueous media. The dry micelles arereconstituted and mobilized when wetted by injecting an aqueous solutioninto the catheter, either during the process of preparing the ballooncatheter for use, or during actual use.

The micelles are infused into tissue surrounding the balloon whenpressurized fluid within the balloon leaks through the wall of theballoon. In a more basic embodiment, a balloon catheter can be providedwith a coating of micelles, in dry, reconstituted or original form onthe outer surface of a porous balloon wall.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a double-walled balloon catheter with a reservoir ofdry micelles.

FIGS. 2 and 3 illustrate a method of operating the balloon catheter ofFIG. 1.

FIGS. 4, 5 and 6 illustrate a method of operating the balloon catheterof FIG. 1.

FIG. 7 illustrates a double-walled balloon catheter with the reservoirof dry micelles, in which both the inner and outer balloons are porousballoons.

FIGS. 8 and 9 illustrate a balloon catheter system in which a reservoirof micelles is disposed within a balloon inflation lumen.

FIGS. 10, 11, 12 and 13 illustrate a balloon catheter system with aproximally located micelle reservoir.

FIG. 14 illustrates an alternative method of wetting the dry micelleformulation in the system of FIGS. 10 through 13.

FIG. 15 illustrates a balloon catheter system in which the reservoir ofmicelles is disposed within a proximal storage chamber within thecatheter handle.

FIG. 16 illustrates the system of FIGS. 10 through 13 modified byplacement of the micelle storage chamber between the three-way valve andthe coiled tube chamber.

DETAILED DESCRIPTION OF THE INVENTIONS

FIG. 1 illustrates a double-walled balloon catheter 1 with a porouswalled outer balloon 2 disposed over an inner balloon 3 (which may beporous or non-porous) mounted on the distal end 4 of the catheter, and areservoir 5 of dry micelles within the balloon catheter, disposedbetween the inner and outer balloons in the inter-balloon space 6. Thedry micelles may be deposited in a reservoir without substantialadditional media, or may be suspended in a dry hydrogel or otherstabilized non-aqueous media. Within the catheter body, a first lumen 7communicates from the proximal end 8 to the inner balloon 3, and asecond lumen 9 communicates from the proximal end of the catheter to thespace between the inner balloon and outer balloon. The porous outerballoon may comprise standard balloon materials such as nylons, blockco-polymers (PEBAX), urethanes, PET, PE (HMWPE, LLDPE, etc.), withnumerous pores in the size range of 100 to 5000 nm (0.1 to 5 microns),and may be compliant (elastomeric and conformable to the vessel wall) ornon-compliant, while the inner balloon may be non-porous or porous, andalso may be elastomeric and conformable to the vessel wall (or outerballoon) or non-compliant, though at least one of the inner or outerballoons is preferably non-compliant for devices intended forangioplasty. For angioplasty, the balloon is preferably nylon, about 20microns thick (0.8 mil thick), with holes 2 to 5 microns in averagediameter (measured on the inside surface of the balloon), up to 100holes of 5 micron diameter or up to 200 holes of 2 micron diameter (or amix of variously sized holes), an overall length of 20 mm and anexpanded diameter of 3 mm. For other purposes, such as treatment ofperipheral blood vessels, the balloon may range from 1.5 to 28 mm indiameter and 5 mm to 200 mm or more. The proximal end 10 of the catheterincludes the Luer fittings 11 and 12, in fluid communication with theinner balloon and outer balloon, respectively, and reservoirs 13 and 14which are filled with a physiologically acceptable aqueous solution suchas saline, ringers solution or PBS, contrast media (Ultravist® forexample) and distension media such as dextran, or other commonpharmaceutical excipients such as polypeptides or polysaccharides.

In use, after preparing the balloon catheter and patient, the ballooncatheter is navigated to a target site within the patient's vasculatureand inflated in order to open an occlusion or restriction at the targetsite. As illustrated in FIGS. 2 and 3, the outer balloon may bepressurized to several atmospheres of pressure, through the inflationlumen 9 aligned with space between the outer balloon and the innerballoon. This inflation will fill the inter-balloon space 6 with aqueoussolution, exerting pressure sufficient to force an occluded target siteopen, while also creating an environment in which the micellepreparation in micelle reservoir 5 is reconstituted or and the micelleswithin the preparation are mobilized. During this step, a small portionof the micelles may be forced from the catheter, as illustrated by thediffuse mass 15 of micelles shown outside the outer balloon. Afterangioplasty (or stent deployment) has been performed to the satisfactionof the interventionalist, while maintaining pressure within the outerballoon (which can be accomplished by blocking the proximal Luer fittingwith a small valve) to prevent back leakage of the fluid in the outerballoon, the inner balloon is inflated slowly to force the micelles andfluid out of the outer balloon through the porous wall of the outerballoon, as shown in FIG. 3. Pressure may be maintained for a minute ortwo (for coronary arteries) or for several seconds to a few minutes (inthe peripheral arteries) in embodiments in which the balloons arenon-perfusing (that is, the balloon does not allow blood flow to flowpast the balloon while inflated), and even longer when the cathetersystem is embodied in a perfusing balloon system, to force many of themicelles from the reservoir 5 into the blood vessel, as represented bythe diffuse mass of micelles 15.

In an alternative method of use, the inner balloon may be used as theballoon which is pressurized to affect the angioplasty or stentdeployment as illustrated in FIGS. 4, 5 and 6. In this case, as shown inFIG. 4, the vascular surgeon will inflate the inner balloon throughinflation lumen 7, leaving the micelle reservoir dry and intact. Afterangioplasty (or stent deployment) has been performed to the satisfactionof the vascular surgeon or interventionalist, the vascular surgeon willdeflate the inner balloon, as shown in FIG. 5, and fill the outerballoon with sufficient aqueous solution to reconstitute the micellepreparation and mobilize or suspend the micelles. Some micelles may beflushed from the outer balloon at this point. As shown FIG. 6, whilemaintaining pressure within the outer balloon to prevent back-leakage ofthe fluid in the outer balloon, the vascular surgeon will re-inflate theinner balloon 3 to force the micelles and fluid out of the outer balloonthrough the porous wall of the outer balloon.

FIG. 7 illustrates a double-walled balloon catheter with the reservoirof dry micelles, in which both the inner balloon 16 and outer balloon 2are porous balloons. Using the catheter of FIG. 7 configured with aporous inner balloon, the inner balloon may be used as the balloon whichis pressurized to affect the angioplasty or stent deployment. In thiscase, the vascular surgeon will inflate the inner balloon 3 throughinflation lumen 7, and leakage of solution from the inner balloon to theinter-balloon space 6 and the micelle reservoir will wet and mobilizethe micelles. The continued pressurization of the inner balloon toaccomplish the angioplasty or stent expansion will result in flow ofaqueous solution through the porous inner balloon, through the spacebetween the balloons and through the porous wall of the outer balloon,thus carrying micelles out of the catheter and into contact with theblood vessel walls.

Though pre-inflation of balloon catheters is not universally encouraged,the catheter maybe prepared, prior to insertion into the vasculature ofa patient by filling the catheter with an aqueous solution, such assaline (or ringers solution, contrast media (Ultravist for example) anddistension media such as dextran), and removing any excess solution fromthe catheter by drawing back fluid through the inflation port. This mayinclude drawing a substantial amount of the micelles from the catheterinto a syringe, mixing the aqueous solution and micelles within thesyringe outside the catheter, and re-injecting the micelle/aqueoussolution mixture into the catheter. The outer balloon may be filled fora period of time to allow reconstitution, and then drained through theinflation lumen (the process may result in drawing some of the micellesinto the inflation lumen). If pre-inflation is performed by the vascularsurgeon, any of the three methods described above may be used.

FIGS. 8 and 9 illustrate a balloon catheter with a micelle reservoirdisposed within an inflation lumen. The catheter 17 includes a balloon18, which has porous walls and is comparable to the outer balloon ofFIG. 1, and an inflation lumen 19 in communication with the balloonvolume 20 and an inflation port at the proximal end of the catheter. Themicelle reservoir 21 is disposed with the inflation lumen 19, coated onthe walls of the lumen or disposed in an enlarged segment of the lumenwhich can serve as a mixing chamber. Although illustrated in theinflation lumen near the distal end of the balloon, the reservoir may belocated more proximally in the inflation fluid pathway, including theinflation lumen, the inflation pathway in the handle of the catheter, orin a separate chamber attached to the proximal handle, between theinflation lumen (or a secondary lumen) and the inflator used to inflatethe balloon. In this device, flow of inflation fluid serves to wet andmobilize the micelles, which are then entrained in the inflation fluidand carried into the balloon, as shown in FIG. 9, and then out throughthe pores of the balloon with that portion of inflation fluid whichescapes the balloon. In this embodiment, an inner balloon can also beprovided as illustrated in FIGS. 4 through 6, and inflated to force muchof the fluid and entrained micelles through the walls of the balloon 18.

FIG. 10 illustrates a balloon catheter system with a proximally locatedmicelle reservoir. In this configuration, the catheter 17 includes thecatheter body 22, handle 23, and a balloon 18, which has porous wallsand is comparable to the outer balloon of FIG. 1. The micelle reservoir24 is disposed within a micelle storage chamber 25, in fluidcommunication with the balloon catheter lumen (within catheter 17)through the three-way valve 26. Opposite the micelle storage chamber 25,the three-way valve communicates with the coiled tube suspension chamber27. The coiled tube suspension chamber is disposed between the three-wayvalve 26 and the balloon inflation device 28 (sometimes referred to asan endoflator). The inflation device is a finely calibrated syringe witha chamber 29, plunger 30 and plunger handle 31 operable to draw fluidinto the chamber and force fluid from the chamber. The inflator includesa meter 32 which accurately displays the pressure of fluid, and theamount of fluid, injected into the balloon catheter. The three-way valve26 is operable to selectively align the coiled tube chamber, and theinflator, with the drug delivery lumen within the catheter 17 or themicelle storage chamber 25. A second three-way valve 33 is disposedbetween the coiled tube suspension chamber 27 and the inflator 28. Theinflator may be filled from a fluid source connected to the secondthree-way valve. A pressure relief valve 34 may be provided to avoidover-pressurization of the system. A filter 35 may be provided at theproximal end of the catheter, at the output of the micelle storagechamber, at the output of the three-way valve (between the three-wayvalve and the catheter body) or between the coiled tube micelle chamberand the three-way valve 26, to prevent any agglomeration of micellesfrom passing into the catheter and ensure that only small particles arepassed into the balloon. The filter is preferably a static 0.45 micronfilter, but may be as small as a 0.1 micron (100 nanometer). The micellestorage chamber 25 is preferable collapsible, so that withdrawal of themicelles after injection of reconstituting fluid is facilitated. Themicelle storage chamber may be a collapsible pouch, a cylinder with aneasily movable base, or a syringe which must be operated in tandem withthe inflator to push the reconstituted suspension from the chamber asthe inflator is used to withdraw the suspension. The micelle storagechamber may include a relief valve or vent to enable degassing andfacilitate filling. The micelle storage chamber 25 is preferabletransparent, so that complete reconstitution and emptying into thecoiled tube suspension chamber can be visually confirmed. The coiledtube chamber has an inner diameter of 1 to 2 mm, and a length of about300 mm. Limiting the diameter to 2 mm or less severely minimizes themixing or osmosis of micelles into the inflator fluid, so that theconcentration of the suspension in the coiled tube chamber is notdiluted when inflator fluid is forced into the coiled tube chamber. Thecoiled tube chamber is coiled merely for compactness. The overall innervolume of the coiled tube is preferably 1 to 2 ml volume of micellesuspension. (The coiled tube suspension chamber and the micelle storagechamber are thus distinguished by their separate functions and distinctstructure. The micelle storage chamber is used to store the micelles forextended periods prior to use (after manufacture, in shipping andstorage for the shelf life of the micelles formulation in itslyophilized condition). The coiled tube suspension chamber is usedintra-operatively, to briefly store the micelles suspension immediatelyprior to delivery through the catheter and balloon, and is sized anddimensioned to limit mixing of the suspension with the inflator fluidheld in the inflator chamber, which it abuts at the boundary of thesuspension bolus and the inflation fluid.)

Thus, FIGS. 10 through 13 show a balloon catheter system for delivery ofdrugs or therapeutic agents to a blood vessel from a dry reservoirstored at the proximal end of the catheter. The balloon cathetercomprises a catheter body with a distal end adapted for insertion intothe vasculature of a patient, a porous balloon disposed on the distalend. The proximal end of the balloon catheter has a lumen extending fromthe proximal end to the balloon. The proximal end is adapted forconnection to a fluid source. The system also includes a storage chamberwith a reservoir of dry drug delivery vesicles, and an inflator andsuspension chamber in fluid communication with an inflator. Thesecomponents are selectively aligned in fluid communication with eachother through a valve operable to selectively connect the storagechamber to the suspension chamber or the lumen of the catheter. Theinflator is operable to fill the storage chamber with fluid toreconstitute the dry drug delivery vesicles into a fluid suspension ofdrug delivery vesicles and draw the fluid suspension into the suspensionchamber, when the valve is positioned to connect the storage chamber tothe suspension chamber, and the inflator is operable to force thesuspension from the suspension chamber through the catheter lumen andporous balloon to the blood vessel.

In use, the system of FIG. 10 is operated in several steps. Afterstandard preparation of the catheter, which may include flushing thecatheter with water or saline, the operator fills the inflator chamberwith fluid, and fills the coiled tube suspension chamber with fluid. Asshown in FIG. 11, the operator turns the three-way valve 26 to align theinflator and coiled tube suspension chamber 27 with the micelle storagechamber 25, and forces the fluid into the micelle storage chamber 24 byoperating the inflator handle. The micelle storage chamber is depictedin a distended state, to illustrate that it has been filled with fluid.Filling the micelle storage chamber with fluid will reconstitute themicelles in the micelle storage chamber and create a suspension that canbe moved into the catheter. Next, as shown in FIG. 12, the three-wayvalve 26 is maintained in position to align the inflator and coiled tubesuspension chamber 27 with the micelle storage chamber 25, and thesuspension of micelles in a small bolus 36 is drawn into the coiled tubesuspension chamber 27. (The micelle storage chamber 25 is depicted in acollapsed state, to illustrate that its contents have been withdrawn.)Routine steps are then taken to ensure that no gas is entrained in themicelle suspension. Next, as shown in FIG. 13, the three way valve ismanipulated to align the coiled tube suspension chamber and inflatorwith the catheter lumen, and the operator pushes the inflator handleinto the inflator chamber to force additional fluid into the coiled tubesuspension chamber and through to the catheter. The suspension that hadbeen drawn into the coiled tube suspension chamber 27 (FIG. 12) ispushed, in a substantially intact bolus 36, into the catheter and thusinto the balloon. If not already flushed of air, this step may serve toflush the catheter and balloon prior to insertion into the body andnavigation into the blood vessel to be treated. When flushed, thecatheter is inserted into the vasculature and navigated to the bloodvessel to be treated. The operator continues to pressurize the inflator,and thus pressurize the balloon, as necessary to force the suspension,and the suspended micelle formulation, through the wall of the balloonand into body tissue surrounding the balloon. The delivery of fluid cancontinue until inflation fluid (from the inflator, which may be acontrast fluid) exits the balloon. The inflation fluid, or a flushingfluid delivered using the inflator, preferably includes contrast agent(iodinated radiocontrast agents, e.g. ionic agents like diatrizoate ormetrizoate or non-ionic agents like iopamidol, iopromide, or iodixanol)so that the arrival of the inflation fluid at the balloon pores, andthus complete ejection of the micelle suspension, can be visuallyconfirmed under fluoroscopy.

The method may be modified by injecting fluid into the micelle storagechamber from a syringe separate from the inflator, as shown in FIG. 14,which shows the micelle reservoir 24 within the micelle storage chamber25, catheter 17, the coiled tube suspension chamber 27, the ballooninflation device 28 and its chamber 29, plunger 30, plunger handle 31,meter 32 and the second three-way valve 33 as in FIG. 10, and theadditional syringe 37 may be provided, and connected to the micellestorage chamber through the four-way valve 38. In this system, thefour-way valve 38 is positioned to align the syringe in fluidcommunication with the micelle storage chamber, then the syringe isoperated to fill the micelle storage chamber with fluid and the four wayvalve is then turned to align the coiled tube suspension chamber 27 tothe micelle storage chamber, and operation is thereafter performed asdescribed in relation to FIGS. 10 through 13. Other means for fillingthe micelle storage chamber with reconstituting fluid may be used,included injection through a self-sealing membrane in the chamber wall,a needle port, or the like.

The proximal components of the system, including the micelle chamber,coiled tube suspension chamber, filter and three-way valve, may beprovided in a single housing to facilitate handling and operation of thesystem. This is illustrated in FIG. 15, which shows the micelle storagechamber 25 and coiled tube isolation reservoir 27 and, optionally, thethree-way valve 26 disposed in the handle 39. This configurationprovides a conveniently operable system with the micelle reservoirstored within the handle of the catheter to be used to deliver themicelle formulation to the body through the balloon. The system isassembled after the micelle formulation is filter sterilized anddeposited in the micelle storage chamber. After the micelle storagereservoir is installed in the handle and sealed to the valve, the entirecatheter may be sterilized with standard ETO sterilization or othermethods that would otherwise degrade the micelle formulation.

The system may be modified by placing the micelle storage chamberbetween the three-way valve and the coiled tube chamber, as shown inFIG. 16, which shows the micelle reservoir 24 within the micelle storagechamber 25, catheter 17, the coiled tube suspension chamber 27, theballoon inflation device 28 and its chamber 29, plunger 30, plungerhandle 31, meter 32 and the second three-way valve 33 as in FIG. 10. Inthis system, the micelle storage chamber is positioned between thethree-way valve and the coiled tube chamber. The inflator is operated tofill the micelle storage chamber with fluid and withdraw the resultingsuspension into the coiled tube chamber, and operation is thereafterperformed as described in relation to FIGS. 10 through 13.

Referring again to the system of FIGS. 10 through 13, the purpose of thecoiled tube suspension chamber is to expose the suspension bolus to thepneumatic force of the inflation fluid in the inflator while minimizingmixing. Mixing can also be prevented by replacing the coiled tube with asecond cylinder divided into chambers by a piston. In such anembodiment, a first chamber, in fluid communication with the three-wayvalve 26 and the micelle storage chamber 25, is filled withreconstitution fluid, and the second chamber, closest to the inflator,is filled with fluid and is in fluid communication with the inflator.Operation of the inflation to force the piston back and forth serves toforce the reconstitution fluid into the micelle storage reservoir, andwithdraw the resulting suspension into the cylinder, and thereafterforce the suspension from the first chamber into the catheter withpneumatic pressure applied to the piston from the inflator. Toaccomplish the goal of flushing all the suspension, and also the goal ofproviding the contrast bloom that confirms complete delivery, theinflator provides inflation fluid or contrast through a bypasscommunication around the cylinder to the catheter lumen.

The inflation pressure and inflation duration, in combination with theamount of dry micelle formulation and volume of the reconstitutedmicelle suspension can be controlled to ensure a predetermined dose ofmicelles, and encapsulated drug, are delivered to the body tissuesurrounding the balloon. Pressure applied by the inflator may be two totwenty atmospheres, and the inflator is preferably operated to apply 6to 12 atmospheres of pressure. With suspended micelle formulation in thesuspension chamber, and hole sizes of 2 to 5 microns in the balloon,application of 12 atmospheres for 60 seconds will deliver the entire 1ml of the suspended micelle formulation through the catheter and balloonwall. The parameters may be adjusted to achieve 0.25 to 10 ml over thecourse of 10 to 120 seconds. The dosage of drug or therapeutic agentactually delivered can thus be controlled and predetermined with somecertainty by controlling the amount of drug or therapeutic agent in themicelle formulation disposed in the micelle storage chamber. Forexample, if it is desired to deliver 2 mg of rapamycin to a diseasedportion of a blood vessel, the micelle reservoir containing 2 or 3 mg ofrapamycin can be stored in the micelle storage chamber, reconstitutingthe micelles with fluid to achieve a concentration of 2 mg/ml (that is,1 ml if the micelle storage chamber contains 2 mg total rapamycin),withdrawing 1 ml of fluid into the coiled tube suspension chamber, andforcing the entire 1 ml through the catheter and balloon into the bloodvessel walls.

The micelles used in the catheter systems described above may beformulated and lyophilized using known procedures, or proceduresdeveloped in the future. The micelle reservoir may be disposed withinthe catheter after formulation and lyophilization, or they may beinstalled in an aqueous slurry in the catheter or a catheter component,and lyophilized afterward, whereupon the catheter may be stored forextended periods of time prior to shipment, and wetted just prior to usein a patient, or when the balloon or balloons are inflated within thebody of the patient. The micelles may be loaded with rapamycin or othertherapeutic agents such as rapamycin analogs, ABT-578, zotarolimus,everolimus, biolimus A9, deforolimus (also referred to asridaforolimus), temsirolimus, tacrolimus, pimcrolimus, nitric oxidesynthase, C3 exoenzyme, RhoA inhibitors, tubulusin, A3 agonists, CB2agonists, 17-AAG, Hsp90 antagonists, tyrphostins, cathepsin Sinhibitors, paclitaxel, dexamethasone, ceramides, dimethyl sphingosine,ether-linked diglycerides, ether-linked phosphatidic acids,sphinganines, estrogens, taxol, taxol analogs, actinomycin D,prostaglandins, vitamin A, probucol, Batimastat, Statins, Trapidil,mitomycin C and Cytochalasin B.

The micelles used in the catheter are preferably formed from tri-blockamphiphilic co-polymers of the form A-B-A where A is hydrophobic (PCL(Polycaprolactone) or PLGA (poly(lactic-co-glycolic acid) for example)and B is hydrophilic (PEG, or PEO for example), in which case the Ablock interacts with the micelle core and drugs encapsulated in the coreand the B block forms the shell of the micelle. The micelles may also beformed of tri-block amphiphilic co-polymers of the form A-B-A where A isPLA, PDLLA, PPS, PPO, or Poly(amino acid)s and B=PEG or PEO. Tri-blockcopolymers of the form B-A-B and Di-block copolymers of the form A-B mayalso be used. Additionally, the micelles may be formed with a corepolymer of PCL. The micelles are formed by nano-precipitation, andresult in micelle sizes in the range of 40-120 nm diameter. Rapamycin orother drug particles can be loaded into the micelles by entrapmentduring the initial formation of the micelles. This will result inefficient loading of the drug particles, and a high percentage of thedrug particles in the formulation slurry will become entrapped withinthe micelles. Drug loading may be accomplished by adsorption ormigration of the drug into the micelles after formulation, though thisis not expected to be as efficient as entrapment. The systems andmethods described above can be employed to deliver other small drugdelivery vesicles or delivery vessels in addition to micelles,particularly small dry vesicles that benefit from reconstitutionimmediately prior to delivery, such as nanoparticles and liposomes.Nanoparticles useful in the system include e.g. PCL, PLGA, PLA, PDLLA,PPS, PPO, or Poly(amino acid)s loaded with drugs. Liposomes can includedry powder liposomes made by lyophilization or dry-spraying. The variousreservoirs shown in the various devices may be protected by filling thecatheter or chamber or balloon housing the reservoir with nitrogen orinert gas.

After formulation, the micelles are freeze-dried, or lyophilized. Themicelles may survive intact, or partially collapse into otherstructures. Nonetheless, upon re-wetting, a substantial portion of themicelle population will be mobilized intact. To enhance the survival ofthe micelles, lyophilization may be performed after a lyoprotectant orcryo-protectant, for example, sucrose, glucose, lactose, mannitol,trehalose, may be added to the original micelle mixture. Afterlyophilization, the mixture of the micelles, encapsulated drug withinthe micelles, and the lyoprotectant compound is particularly useful asthe reservoir described above.

The micelles used in this system and method described above should be inthe range of 40 to 250 nm (0.04 to 0.250 micron) generally, and in therange of 60 to 120 nm when formulated from the tri-block copolymermentioned above (PLGA-PEG-PLGA or PCL-PEG-PCL). This size will result ina balance of efficient penetration of the micelles into the artery wallsand sufficient space within the micelles to encapsulate a suitableamount of rapamycin or other therapeutic substance. Use of tri-blockpolymers such as PLGA-PEG-PLGA will provide micelles in the desiredsized range. For micelle doses prepared prior to loading into thecatheter, polydispersity index of the micelle population is preferablyless than 0.2, as measured by a dynamic light diffusion test. This maybe achieved by controlled formulation, filtration or centrifugation ofpolydisperse population of micelles.

For reconstitution of the micelles, an aqueous solution, typically anisotonic solution with or without additional lyoprotectant and/orpharmaceutical excipient, is added to the dry micelle formulation viasyringe, catheter barrel, or tube. The suspension is further mixed, ifrequired, by physical agitation, drawing back and forth into a syringe,or other means.

While the devices and methods described above have been illustrated inthe context of coronary artery treatment and restenosis, they may beused in other vessels in the body, including the peripheral bloodvessels, esophagus, ureters, urethra, sinus, valves, etc., and may beused to deliver a variety of drugs, therapeutic agents, especiallyhydrophobic agents which may be encapsulated in micelles or liposomes.

While the preferred embodiments of the devices and methods have beendescribed in reference to the environment in which they were developed,they are merely illustrative of the principles of the inventions. Theelements of the various embodiments may be incorporated into each of theother species to obtain the benefits of those elements in combinationwith such other species, and the various beneficial features may beemployed in embodiments alone or in combination with each other. Otherembodiments and configurations may be devised without departing from thespirit of the inventions and the scope of the appended claims.

We claim:
 1. A system for delivery of drugs or therapeutic agents to ablood vessel, said system comprising: balloon catheter comprising acatheter body with a distal end adapted for insertion into thevasculature of a patient, a porous balloon disposed on the distal end,and a proximal end adapted for connection to a fluid source, and a lumenextending from the proximal end to the balloon; a storage chamber with areservoir of dry drug delivery vesicles; an inflator; a suspensionchamber in fluid communication with an inflator; a valve operable toselectively connect the storage chamber to the suspension chamber or thelumen of the catheter; wherein the inflator is operable to fill thestorage chamber with fluid to reconstitute the dry drug deliveryvesicles into a fluid suspension of drug delivery vesicles and draw thefluid suspension into the suspension chamber, when the valve ispositioned to connect the storage chamber to the suspension chamber, andthe inflator is operable to force the suspension from the suspensionchamber through the catheter lumen and porous balloon to the bloodvessel.
 2. A system of claim 1, wherein the reservoir of dry drugdelivery vesicles comprises micelles loaded with rapamycin or rapamycinanalogs.
 3. A system of claim 1, wherein the reservoir of dry drugdelivery vesicles comprises micelles loaded with ABT-578, zotarolimus,everolimus, biolimus A9, deforolimus, temsirolimus, tacrolimus,pimcrolimus, nitric oxide synthase, C3 exoenzyme, RhoA inhibitors,tubulusin, A3 agonists, CB2 agonists, 17-AAG, Hsp90 antagonists,tyrphostins, cathepsin S inhibitors, paclitaxel, dexamethasone,ceramides, dimethyl sphingosine, ether-linked diglycerides, ether-linkedphosphatidic acids, sphinganines, estrogens, taxol, taxol analogs,actinomycin D, prostaglandins, vitamin A, probucol, Batimastat, Statins,Trapidil, mitomycin C or Cytochalasin B.
 4. A system of claim 1, whereinthe suspension chamber comprises a tube with a diameter of 2 mm or less.5. A system of claim 1, wherein the suspension chamber comprises acoiled tube with a diameter of 1 to 2 mm, and overall length of about300 mm.
 6. The system of claim 1, wherein the valve is a three way valveinterposed between the storage chamber and the suspension chamber, andis operable to align the storage chamber and the suspension chamber influid communication, and is also disposed between the catheter and thesuspension chamber, and is operable to align the catheter lumen andsuspension chamber in fluid communication.
 7. The system of claim 1,further comprising a catheter handle disposed on the proximal end of thecatheter, wherein the storage chamber and the suspension chamber aredisposed within the handle.